Inflammatory diseases represent a large and increasing health burden throughout the world. Chronic inflammatory conditions include autoimmune disorders (rheumatoid arthritis, multiple sclerosis, psoriasis), allergies, periodontists and gastrointestinal inflammatory diseases. These diseases are characterised by an influx of inflammatory cells into the extravascular connective tissue of target organs. In these sites, aberrant activation of circulating and/or resident lymphocytes becomes self-perpetuating and this leads to chronic tissue destruction. The main cells responsible for this destruction are lymphocytes and monocyte/macrophages. This type of inflammation may also be generated by persistent infection (e.g., tuberculosis), in chronic rejection of solid organ transplants and in chronic graft-versus-host disease following bone marrow transplantation.
The recruitment and accumulation of these cells into the target site is regulated by the release of soluble chemokines and by specific adhesion molecules expressed on the extravascular tissues and on the migrating lymphoid/myeloid cells. Activation of macrophages and the proliferation of lymphocytes, particularly T lymphocytes, within these sites leads to the production of pro-inflammatory molecules; chemokines, cytokines, enzymes, reactive oxygen species (ROS), leukotrienes and prostaglandins.
Chemokines such as RANTES, MIP-1alpha/beta, MIP-3alpha/beta, MCP-1 to MCP-4, TARC, PARC, lymphotactin and fractalkine are released at inflammatory sites and recruit monocytes and T cells. Cytokines such as TNF, INFgamma, IL-1beta, IL-2, IL-12 and IL-18 are released which drive cell proliferation. Multiple enzymes are activated in these inflammatory cells and these include LTA4 hydrolase, 5-LO, COX-2 and PLA-2. Tissue-degrading enzymes such as metalloproteases and cysteine proteases are also released. Gene expression of many of these molecules is regulated by the ubiquitous transcription factor NFkB. The anti-inflammatory activity of steroids is largely through inhibition of activated NFkB but they also affect other pathways which results in toxic side effects. There are various modes of treatment for chronic inflammatory conditions but they largely consist of using a non-steroidal anti-inflammatory agent initially followed up by steroids, cyclosporin/FK506 or, in severe conditions, nucleoside synthesis inhibitors and alkylating agents.
In addition to chronic inflammatory diseases, there are several clinically-important conditions associated with acute inflammation. These include acute respiratory distress syndrome (ARDS), pancreatitis and the allergic conditions of rhinitis and urticaria. Acute transplant rejection and graft-versus-host disease are also a result of rapid inflammatory responses. Lymphocytes are important in priming many acute inflammatory responses due to antibody production (IgE, complement fixing IgG or IgM) and cytokine production but granulocytes and mast cells tend to play a more direct role in the pathogenesis. Monocyte products also drive acute inflammation.
Agents which can inhibit monocyte/macrophage and lymphocyte activation and subsequent lymphocyte proliferation would be useful in treating inflammatory disorders. Such agents would reduce the number of cells in the inflammatory site and the levels of pro-inflammatory mediators.